Signal Transduction

Edited by: Thomas W. Durso SEEKING STATs: Anne-Marie O’Farrell, left, and Alice Mui of DNAX found STAT5, a protein that responds to the cytokine interleukin-3. A.L.-F. Mui, H. Wakao, A.-M. O'Farrell, N. Harada, A. Miyajima, "Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs," EMBO Journal, 14:1166-75, 1995. (Cited in more than 110 publications as of April 1997) Comments by Alice L.-F. Mui, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, Calif. Interleukin-3 (IL-3) is a cytokine that regulates hemopoiesis, the formation of blood cells in the body. In this paper, Alice L.-F. Mui, a senior research associate at the DNAX Research Institute of Molecular and Cellular Biology in Palo Alto, Calif., examined what happens after IL-3 binds to its receptor. "I wanted to find out what the next step in the signal-transduction cascade was," she states. "How does receptor activation lead eventually to gene induction and changes in the phenotype of the cells?" Mui was studying a protein that was rapidly phosphorylated after IL-3 stimulation. Its molecular weight and phosphorylation kinetics were similar to those of a protein known as STAT1, for "signal transducers and activators of transcription," discovered by James Darnell at Rockefeller University (C. Schindler et al., Proceedings of the National Academy of Sciences, 89:7836-9, 1992); however, Darnell's protein did not respond to IL-3. Mui continued to search and discovered that a STAT homolog now known as STAT5 is responsive to IL-3. "STAT proteins are the direct link from the receptor to the nucleus," she remarks. "In most other signal-transduction cascades, there are more multiple steps. . . . In contrast, STAT proteins exist before activation in the cytoplasm as latent forms and become directly recruited to the receptor upon cytokine stimulation. This leads to phosphorylation and dimerization of the STAT protein, and activated STAT dimers translocate to the nucleus, where they bind to specific sequences in the promoters of target genes and mediate gene transcription. "The fact that it is a direct link from the receptor to the nucleus was exciting to many people. It might be a way for cytokine signaling pathways to be specific to each cytokine. The big question in the field is how signal specificity is effected. . . . When the STAT proteins were discovered, people thought this might be a way that each receptor could exert a specific effect. . . . But it's much more complicated than that. Currently, a lot of work is directed toward looking at how STATs function and whether it could mediate cytokine specificity." Both Mui's team and another published the STAT5 sequence at about the same time, and a year later, a separate group published the sequence of the human version of the clone. "Usually it's the human gene that generates interest," Mui explains. Still, she offers several reasons to explain her paper's high number of citations: "STAT5 is important, because there was a lot of competition to try to find which STAT, if such existed, responded to IL-3. The IL-3 receptor is interesting, as it shares one component with the receptors for two other cytokines. STAT5 also functions in the pathway of those other cytokines. My guess is that this was the first description of STAT5 being downstream of IL-3. "Our studies also differed from [the other teams'] in that we found two highly homologous STAT5 genes, and we tried to resolve why two such highly related molecules should exist. We compared their tissue distribution and also assessed their possible functional differences. By correlation with the biological effects known to be mediated by various receptor mutants, we were able to provide a first indication of what role STAT5 might play in cytokine signaling. It's now known that STAT5 is a transcription factor activated by many stimuli in addition to IL-3, and an important issue has become what functions the two STAT5s mediate in these various systems. I think our paper was the first to attempt to address this question." After publishing this paper, Mui sought to determine the specific aspect of IL-3 signaling that is mediated by STAT5 using a dominant-negative STAT5. She found that STAT5 contributes to the ability of IL-3 to support proliferation of IL-3-dependent cells (A.L.-F. Mui, EMBO Journal, 15:2425-33, 1996).

Signal Transduction

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